Fungal infections are major causes of morbidity and mortality. In particular, fungal infections can be life threatening for those with weakened immune systems. Severe systemic fungal infections, such as candidiasis, aspergillosis, histoplasmosis, blastomycosis and coccidioidomycosis are often acquired in hospital settings. Such infections are commonly seen in patients with suppressed immune systems.
For example, patients at risk of fungal infection include neutropaenic patients following chemotherapy and in other oncology patients with immune suppression, immune-compromised due to Acquired Immune Deficiency Syndrome (AIDS) caused by HIV infection, and in patients in intensive care. While there are treatments for candidiasis and aspergillosis, these treatments are plagued by limited efficacy, serious side effects, high expense, and often result in drug resistance.
Classes of established antifungal drugs on the market include: (1) the polyenes (e.g. amphotericin B, nystatin, natamycin), (2) the azoles (e.g. fluconazole, itraconazole, voriconazole), (3) allylamines (e.g. terbinafine), and (4) the newly introduced echinocandins (e.g. caspofungin). Of these classes, only the polyenes, azoles, and echinocandins are used to treat systemic fungal infections. Each of the currently marketed antifungal drugs have major drawbacks, including a lack of broad-spectrum activity, a lack of per oral absorption, undesirable side-effects, low antifungal activity, a lack of fungicidal activity, drug-drug interactions, and high costs. Further, the systemic antifungal, amphotericin B, is highly toxic when administered intravenously, and its side-effects include severe organ damage.
Therefore, there is a pressing need for potent antifungals for both topical and systemic infections. Treatment failures and secondary drug resistance remain common with systemic mycoses. In particular, antifungal drugs with broad spectrum activity against multiple species, per oral absorption, lower amount of side-effects, fungicidal activity, no drug-drug interactions or lower costs or a combination of these are desirable.